PROJECT SUMMARY/ABSTRACT Preeclampsia, the leading cause of premature births and major contributor to maternal and fetal morbidity, affects 5-8% of all pregnancies in the US. Cerebrovascular abnormalities are implicated in 40% of all preeclampsia/eclampsia related deaths; yet the pathophysiological mechanisms involved have not been fully elucidated. The mentored phase of this proposal will test the hypothesis that increases in circulating agonistic antibodies to the angiotensin II Type 1 receptor (AT1-AA) contribute to abnormalities in cerebrovascular function potentially through decreased expression of beta epithelial sodium channel (?ENaC). AT1-AAs are increased in preeclamptic patients and induce hypertension when infused in normal pregnant rats. Compelling evidence suggests that the degenerin family of proteins, composed of ENaCs and acid sensing ion channels (ASICs), play a major role in mechanotransduction in vascular smooth muscle cells. These proteins have been shown to mediate the myogenic response, a mechanism that protects the microvessels and subsequent tissue from damage by reducing intraluminal diameter in response to acute increases in blood pressure. Preeclamptic patients and animal models of preeclampsia display impairments in regulating cerebral blood flow which can contribute to cerebral edema and blood-brain barrier disruption. Indeed, magnetic resonance imaging and computed tomography scans of brains of preeclamptic patients demonstrate characteristics of cerebral edema. Additionally, previous research has shown that ?ENaC is reduced in cerebral arteries isolated from placental ischemic rats that also have impaired myogenic tone, increased blood-brain barrier permeability, and cerebral edema. Because placental ischemic rats have reduced cerebrovascular ?ENaC expression and impaired myogenic tone, and because ASIC2 and ?ENaC are key regulators of the myogenic response, in the R00 phase, I propose to determine whether reductions in ?ENaC and ASIC2 during pregnancy play a role in mediating cerebrovascular abnormalities. I hypothesize that reductions in ?ENaC and ASIC2 during pregnancy lead to impaired myogenic reactivity of the cerebral blood vessels, impaired cerebral blood flow autoregulation, increased blood-brain barrier permeability and edema, and increased susceptibility to seizures. I will utilize genetically modified mice with reduced ?ENaC and/ or ASIC2 to determine whether these degenerin proteins are important in maintaining cerebrovascular function during pregnancy.